Method for producing agglomerates comprising a core-shell structure

ABSTRACT

A process for producing agglomerates with a core/shell structure, in which i) initial agglomerates containing a first particulate solid are prepared; ii) a second particulate solid is agglomerated in the presence of the initial agglomerates with the addition of a binder liquid to give second stage agglomerates and, where appropriate, iii) an nth (n≧3) solid is agglomerated in the presence of the (n−1)th stage agglomerates with the addition of a binder liquid to give nth stage agglomerates.

This application is a 371 of PCT/EP99/09462 filed Dec. 3, 1999.

DESCRIPTION

The present invention relates to a process for producing agglomerateswith a core/shell structure and to the agglomerates obtainable thereby.

Agglomeration is to be understood here to be a process in whichfine-pile substances are clumped together by wetting with a liquid withsimultaneous mechanical agitation to give conglomerates, i.e. pellets orgranules. The resulting agglomerates are assemblages of particles inwhich the original particles are not completely fused together, it beingpossible, for example by microscopic examination, still to recognize theoutlines of some of the individual particles. An agglomerated materialhas numerous advantages over the fine-particle starting material. Thus,certain properties such as strength, size, shape and porosity can beadjusted in a defined manner, which is noticeably advantageous onstorage, transport and metering. Any homogeneities are prevented, thebulk properties are improved and the formation of dust during packagingand transferring is reduced. This increase in quality makes theadditional agglomeration processing step justifiable in the manufactureof numerous products such as drugs.

In what is called agitative agglomeration there is automatic attachmentof the particles together on wetting with liquid on the reaction ofinterfacial forces while the material is agitated mechanically.

A special type of agitative agglomeration is rewetting agglomeration.The basis for this is a 3-phase mixture which consists of a finematerial to be agglomerated and of a suspending liquid and a binderliquid which must not be miscible with one another. The binder liquidmust have the property of wetting the suspended material better thandoes the suspending liquid. The fine material to be agglomerated ispresent in suspended form in the suspending liquid. The binder liquid isthen introduced and interacts with the fine particles and leads toparticle size enlargement. The granules which are formed are removedfrom the reusable suspending liquid, for example using a filtrationapparatus.

Many drugs can be administered in solid form as agglomerates. Thesedissolve in the body over a certain period. The rate of dissolution isdetermined by the area of the drug available for attack by body fluid,i.e. the surface area of the drug. If the surface area is reduced by thedissolution process, a smaller amount of active ingredient is releasedper unit time. However, for most applications a constant rate of releaseof active ingredient is desired. One aspect of the present invention istherefore based on the object of indicating a process for producingagglomerates which show essentially uniform release of active ingredientthroughout the dissolution period.

It is often desirable to produce solid drug forms with more than oneactive ingredient, with the active ingredients being released atdifferent times.

Another aspect of the invention is therefore based on the object ofindicating a process for producing agglomerates which contain differentactive ingredients which are released successively.

DE-A 44 00 295 describes a spherical granulum which is prepared byintroducing lactose particles into a granulating and coating apparatusequipped with a horizontal rotating disk having a flat contactingsurface towards the granula, and spraying a lactose solution duringrotation of the rotating disk. The granulum is useful as carrier fordrugs and foodstuff.

We have found that the above objects are achieved by a process forproducing agglomerates with a core/shell structure, in which i) initialagglomerates containing a first particulate solid are prepared; ii) asecond particulate solid is agglomerated in the presence of the initialagglomerates with the addition of a binder liquid to give second stageagglomerates and, where appropriate, iii) an nth (where n is a positiveinteger ≧3) solid is agglomerated in the presence of the (n−1)th stageagglomerates with the addition of a binder liquid to give nth stageagglomerates. Step iii) is optional. It can, if required, be repeatedone or more times. The value of n starts at 3 and increases by 1 afterevery repetition.

FIG. 1 shows a scanning electron micrograph of a fractured agglomerateproduced according to the invention.

In the process according to the invention a particulate solid isagglomerated in the presence of initial agglomerates. The initialagglomerates act as agglomeration nuclei. It has been found,surprisingly, that it is possible under these conditions for theparticulate solid to become attached in the form of a shell to thepreformed agglomeration nuclei, not to itself with spontaneous formationof new nuclei. The agglomerates obtained in this way are able in turn toact as agglomeration nuclei for the agglomeration of further identicalor different solids.

The agglomerates obtained according to the invention comprise a core andat least one shell disposed on the core. If more than one shell isdesired, optional step iii) is carried out, where appropriaterepeatedly. It is possible in this way to obtain core/shell agglomerateswith two or more, for example three, four or five etc., shells aroundone core. The ratio by weight of core to first shell, or the ratio byweight of the inner shell to the outer shell of a pair of consecutiveshells, is preferably in the range from 1:9 to 9:1, in particular 1:9 to8:2.

The process according to the invention can be carried out asconventional agitative agglomeration, with agglomeration nuclei andparticulate solid being exposed, preferably with the addition of theancillary substances discussed below, to the mechanical agitation whilebeing wetted by the binder liquid. Suitable for this purpose are allconventional types of mixer such as conical mixers, horizontal orvertical mixers or drum mixers, where appropriate with a chopper.

Alternatively, the process according to the invention can be carried outin the form of a rewetting agglomeration. In this case, the clumpingtogether of the particulate solid takes place in the liquid phase.Agglomeration nuclei, particulate solid and, where appropriate,ancillary substances are dispersed in a suspending liquid. Thesuspending liquid must be chosen so that both agglomeration nuclei andon the other hand the particulate solid are essentially insolubletherein. The binder liquid is introduced into this suspension. Binderliquid and suspending liquid must be chosen to be essentially immisciblewith one another. The introduction of the binder liquid can take placedirectly through a nozzle or in the form of an emulsion of binder andsuspending liquids. The binder liquid must be chosen so that it wets theparticulate solid better than does the suspending liquid. On exposure tothe binder liquid, the solid particles interact and agglomerate in theform of a shell around the agglomeration nuclei. Suitable for carryingout the rewetting agglomeration is, for example, a stirred vessel or acontinuously operated cylindrical stirrer as described, for example, inEP-A-0 690 026. Removal of the agglomerates which are formed from thesuspending liquid can take place through any apparatus suitable for thispurpose, for example a filtration apparatus. The agglomerates can thenbe dried.

The nature of the particulate solids in each case is not critical forthe present invention and is subject to essentially no restrictions.Where reference is made herein to a “particulate solid” some of this mayalso comprise a mixture of solids. “Particulate” means that the solid isin the form of separate particles which are subject to essentially nointeractions before the agglomeration. These often comprise hard,brittle, nontacky substances which cannot be directly molded. Exampleswhich may be mentioned are salts such as potassium chloride, ammoniumsulfate, calcium phosphate, diammonium phosphate, potassium phosphate,calcium carbonate; molecular organic compounds such as urea,theophylline, verapamil; three-dimensionally crosslinked compounds suchas zeolites; polymeric compounds such as polyethylene glycols with amolecular weight of, for example, 6000 to 9000, polymers or copolymersof ethylenically unsaturated mono- and dicarboxylic acids such as(meth)acrylic acid or maleic acid, and modified, e.g. wholly or partlyneutralized, variants thereof; etc.

The particle size may vary within wide limits. A general range which maybe mentioned is from 1 to 1000 μm, preferably 1 to 500 μm. Suitableparticle sizes can be obtained by crystallization, mechanicalcomminution of compact forms, e.g. by grinding, chopping, crushing andsublimation.

In preferred embodiments, an active pharmaceutical ingredient, whereappropriate mixed with ancillary substances, is used as particulatesolid in the core and/or at least one shell. Active pharmaceuticalingredient means for the purpose of the invention any substance with adesired effect on the human or animal body or plants. It is alsopossible to employ combinations of active ingredients.

Preferred examples of active ingredients which can be employed for thepurpose of the invention are, inter alia, verapamil, theophylline,ibuprofen, ketoprofen, flurbiprofen, acetylsalicylic acid, paracetamol,nifedipine or captopril.

The particulate solids, in particular active ingredients, can also beadmixed with ancillary substances to construct the core and/or a shell.Suitable ancillary substances are the binders mentioned below. Furtherancillary substances which can be used are extenders and fillers such assilicates or diatomaceous earth, magnesium oxide, titanium dioxide,methylcellulose, sodium carboxymethylcellulose, talc, sucrose, lactose,cereals or corn starch, potato flour, polyvinyl alcohol, Aerosil, etc.It is also possible to add dyes, wetting agents, preservatives anddisintegrants.

The particulate solids present in the core and in the first shell or insubsequent shells preferably differ in at least one chemical and/orphysical property.

These solids may comprise different chemical species. They may alsocomprise mixtures of varying composition or a pure substance and amixture. A typical example thereof is, for example, the application of amixture of a dye with one or more active ingredients and/or ancillarysubstances to a core containing no dye.

In other embodiments, the solids in the core and in the first shell orin two consecutive shells differ in at least one physical property, inparticular in the particle size. In these embodiments the first andsecond particulate solid and/or for at least one value of n the (n−1)thand the nth solid have different particle sizes.

Thus, for example, solids comprising identical substances but differingin at least one physical property, e.g. differing in particle size, canbe employed. This is of interest, for example, in cases where it isdesired to have uniform release characteristics of active ingredients ondissolving the agglomerates produced according to the invention. Thus,for example, it is possible to combine a porous core of solids with alarger particle size and a more compacted shell of solids with a smallerparticle size. The porous core would compensate for the decreasingsurface area on dissolving of the agglomerate and ensure that therelease rate does not decrease significantly. It is generally preferredfor the solid in the first shell to have a smaller particle size thanthe solid in the core, or for the solid in an outer shell to have asmaller particle size than the solid in the underlying shell.

The second particulate solid therefore preferably has a smaller particlesize than the first particulate solid and/or for at least one value ofn, in particular for all values which n can assume, the nth particulatesolid has a smaller particle size than the (n−1)th particulate solid.

The first particulate solid preferably has a particle size of 50-800 μm,in particular 100-500 μm, in the direction of the longest dimension. Thesecond particulate solid preferably has a particle size of less than 500μm, in particular less than 50 μm. The second particulate solidgenerally has a particle size of at least 1 μm.

It is possible in a specific case for the first and second particulatesolid or the particulate solids in consecutive shells to be identical.Thus, it may be advantageous to apply not one shell in a very thicklayer but several shells in layers less thick. Further advantages mayoccasionally be obtained when the agglomeration nuclei are gradedaccording to size before the further agglomeration, in which case onlynuclei of a particular size or of a particular size range are usedfurther. It is possible in this way to obtain agglomerates with anarrower size distribution than in a one-stage agglomeration.

The agglomeration takes place with the addition of a binder liquid. Ifmore than one shell is constructed around an agglomeration nucleus inthe process according to the invention, the binder liquids employed inthe individual steps may be identical or different. The binder liquidmay be selected from a wide range of liquids depending on the solid tobe agglomerated. It is essential that the binder liquid is able to wetadequately the solid to be agglomerated. A measure which can be definedfor the wetting ability of a binder liquid is a contact angle δ, alsoreferred to as wetting angle, which the liquid forms with the surfacearea of the solid. The contact angle δ is preferably below 90°, inparticular below 60°.

The binder liquid can be chosen so that the solid to be agglomerated issoluble in it. It is self-evident that in this case the amount of binderliquid which can be used must be insufficient to dissolve completely thesolid to be agglomerated. In general, less than 20% by weight,preferably 1 to 15% by weight, based on the weight of the solid to beagglomerated, of dissolving binder liquid are employed. During theagglomeration, the added binder liquid partly dissolves the solid to beagglomerated and, after the drying of the agglomerates, crystal bridgesbetween the particles remain and hold the particles together.

In the particular case where the solid to be agglomerated is onlyslightly soluble or insoluble in the binder liquid it is possible to addto the binder liquid and/or to the solid to be agglomerated a substancewhich is soluble in the binder liquid and which leads, after the dryingof the agglomerates, to material bridges between the particles. Examplessuitable for this purpose are organic and inorganic salts such as sodiumchloride, potassium chloride, potassium nitrate, sodium nitrate orsodium acetate, organic acids which are solid at room temperature, suchas ascorbic acid, citric acid, adipic acid; sugars, e.g. monosaccharidessuch as glucose, fructose; di- or oligosaccharides such as sucrose orlactose; or urea.

In preferred embodiments, a polymeric binder is added to the binderliquid and/or the solid to be agglomerated. Examples of suitablepolymeric binders are polyethylene glycols, polypropylene glycols andmixed polymers thereof, polyvinyllactam, in particularpolyvinylpyrrolidone (PVP), copolymers of vinyllactams such asN-vinylpyrrolidone, N-vinylpiperidone and N-vinyl-e-caprolactam,N-vinylpyrrolidone with (meth)acrylic acid, (meth)acrylic acid esters,vinyl esters, in particular vinyl acetate, copolymers of vinyl acetateand crotonic acid, partially hydrolyzed polyvinyl acetate, polyvinylalcohol, poly(hydroxyalkyl acrylates), poly(hydroxyalkyl(meth)acrylates), polyacrylates and poly(meth)acrylates, copolymers ofmethyl (meth)acrylate and acrylic acid, cellulose esters, celluloseethers, in particular methylcellulose and ethylcellulose,hydroxyalkylcelluloses, in particular hydroxypropylcellulose,hydroxyalkylalkylcelluloses, in particular hydroxypropylethylcellulose,cellulose phthalates, in particular cellulose acetate phthalate andhydroxypropylmethylcellulose phthalate, and mannans, especiallygalactomannans. It is also possible to use biodegradable polymers suchas polyhydroxyalkanoates, e.g. polyhydroxybutyric acid, polylactic acid,polyamino acids, e.g. polylysine, polyasparagine, polydioxane andpolypeptides. The polymeric binders employed may be hydrophilic orhydrophobic depending on the nature of the solid to be agglomerated. Thebinders may be soluble or dispersed or dispersible in the particularbinder liquid.

The initial agglomerates used in the process according to the inventioncomprise a first particulate solid which can be produced by anyagglomeration process. It is preferred for the initial agglomerates tobe produced by agglomerating the first particulate solid by means ofagitative agglomeration or rewetting agglomeration using a binderliquid. Reference may be made to the above statements in thisconnection, but the agglomeration of the first particulate solid takesplace in the absence of agglomeration nuclei with spontaneous nucleusformation. It is particularly advantageous to carry out theagglomeration of the first particulate solid to give initialagglomerates in the same apparatus in which the attachment of the secondand, where appropriate, further particulate solids subsequently takesplace. Thus, the first particulate solid can be agglomerated with theaddition of a binder liquid to give initial agglomerates. The secondparticulate solid is added with further binder liquid or another binderliquid and agglomerated to form a shell around the initial agglomeratesacting as agglomeration nuclei. If further shells are desired, the aboveprocedure is repeated one or more times.

The initial agglomerates normally have a size of from 50 to 1500,preferably from 100 to 1000, μm. In a particular case where a narrowagglomerate size distribution is desired, the initial agglomerates canbe graded according to size. Only initial agglomerates of a particularsize or of a particular size range are used further. On attachment offurther shells, the agglomerates from the preceding stage can likewisebe fractionated according to size.

The process according to the invention has a variety of possibleapplications. For use in the pharmaceutical sector, for example, it ispossible to produce agglomerates with a density gradient which can bechanged radially outward from the center and with which the amount ofactive ingredient released can be influenced not only by the diameterbut also by a diameter-dependent porosity. It is also possible by theprocess according to the invention to produce solid drug forms in whichtwo different active ingredients are combined and are releasedsuccessively. For example, the active ingredient in an outer shell maydissolve in the stomach, and the active ingredient in an inner shell orin the core may dissolve in the intestine. It is also possible by theprocess according to the invention for incompatible active ingredientsto be converted into a single dosage form.

In the detergent sector, for example, an incrustation inhibitor and ableach can be applied as shells on a surfactant core. The invention isillustrated in detail by the following examples.

EXAMPLE 1

This example illustrates the production of a core/shell agglomerate withcrystalline theophylline (average particle size 100 μm) in the core andpowdered theophylline (average particle size 10 μm) in the shell. Theagglomeration takes the form of a rewetting agglomeration withcyclohexane as suspending liquid and water as binder liquid.

The agglomeration was carried out in a double-wall glass container witha capacity of 21 under ambient conditions. The stirring was effected bya stirrer with four blades which were adjusted at an angle of 45° andattached offset by 90°. 3 sheets with a width of 15 mm were introducedinto the container as baffles.

700 ml of cyclohexane and 140 g of crystalline theophylline wereintroduced into the container. The crystalline theophylline wasdispersed uniformly in the cyclohexane by stirring at 700 rpm. 73 ml ofdeionized water were introduced under a pressure of 2 bar through anozzle which had a diameter of 1.4 mm and was fixed 6 cm below thesurface of the suspension over the course of 30 min. The nuclei producedin this way were left in the suspension.

While stirring continuously at 700 rpm, the suspension was diluted with700 ml of cyclohexane. Then 280 g of powdered theophylline wereintroduced through a funnel into the container. Subsequently, 109.2 mlof deionized water were added over the course of 45 min under the sameconditions as previously.

The stirring container was then disassembled and its contents werefiltered off through a suction funnel. The agglomerates were dried inair. Core/shell agglomerates with a porous core of crystallinetheophylline and a compacted shell of powdered theophylline wereobtained. FIG. 1 shows a scanning electron micrograph of a fracturedagglomerate.

EXAMPLE 2

Core/shell agglomerates with a core of calcium carbonate (particle sizeabout 4 μm) and a shell of a mixture of calcium carbonate (particle sizeabout 4 μm) and riboflavin C were produced. Both core and shellcontained polyvinylpyrrolidone (K value 30) as binder.

1000 g of calcium carbonate and 50 g of polyvinylpyrrolidone wereintroduced into the mixing vessel of an Eirich mixer and initially mixedfor 2 min with maximum energy input. 160 g of water were added using aspray bottle over the course of 40 s with maximum energy input. Mixingwas then continued for 10 s without further addition of liquid.

4000 g of calcium carbonate, 300 g of riboflavin C and 215 g ofpolyvinylpyrrolidone were initially mixed for 5 min. 1050 g of thismixture were added to the agglomerate nuclei produced as above. Mixingwas carried out for 48 s with a star-type agitator at an agitator speedof 1500 rpm and a plate speed of 84 rpm with the vessel and agitatormoving in opposite directions. Over the course of 25 s, 100 g of waterwere added using a spray bottle, and then mixing was continued for 74 s.Core/shell agglomerates with a core of uncolored calcium carbonate and ashell of yellow-colored calcium carbonate were obtained.

We claim:
 1. A process for producing agglomerates with a core/shellstructure, in which i) initial agglomerates containing a firstparticulate solid are provided; ii) a second particulate solid isagglomerated in the presence of the initial agglomerates and,optionally, iii) an nth (n≧3) particulate solid is agglomerated in thepresence of the (n−1)th stage agglomerates,  wherein the agglomerationin step ii) and/or iii) takes place by a) dispersing the initialagglomerates and the second particulate solid or the (n−1)th stageagglomerates and the nth particulate solid, respectively, in asuspending liquid in which both the first particulate solid and thesecond particulate solid or the (n−1)th particulate solid and the nthparticulate solid, respectively, are essentially insoluble the b)introducing into the suspending liquid, a binder liquid which isessentially immiscible with the suspending liquid, and c) drying theresulted agglomerates of step b) to obtain a core/shell structure.
 2. Aprocess as claimed in claim 1, wherein the first and second particulatesolid and/or for at least one value of n the (n−1)th and the nthparticulate solid have different particle sizes.
 3. A process as claimedin claim 2, wherein the second particulate solid has a smaller particlesize than the first particulate solid and/or for at least one value of nthe nth particulate solid has a smaller particle size than the (n−1)thparticulate solid.
 4. A process as claimed in claim 2, wherein the firstand second and/or for at least one value of n the (n−1)th and nthparticulate solid are of identical chemical composition.
 5. A process asclaimed in claim 1, wherein the first particulate solid has a particlesize of 50-800 μm.
 6. A process as claimed in claim 1, wherein thesecond particulate solid has a particle size of less than 500 μm.
 7. Aprocess as claimed in claim 1, wherein the agglomeration in step ii)and/or iii) takes place in the presence of a bridge-forming substanceand/or of a binder.